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A large lung gene expression study identifying IL1B as a novel player in airway inflammation in COPD airway epithelial cells

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Abstract

Background

Chronic obstructive pulmonary disease (COPD) is a chronic and progressive lung disease characterized by a mixture of small airway disease and lung tissue parenchymal destruction. Abnormal inflammatory responses to cigarette smoking and other noxious particles are generally thought to be responsible for causing of COPD. Since airway inflammation is a key factor in COPD progress, it is crucial to unravel its underlying molecular mechanisms. Unbiased analysis of genome-wide gene expression profiles in lung small airway epithelial cells provides a powerful tool to investigate this.

Methods

Gene expression data of GSE611906, GSE20257, GSE8545 were downloaded from GEO database. All 288 lung small airway samples in these cohorts, including donors with (n = 61) and without (n = 227) COPD, were chosen for differential gene expression analysis. The gene ontology (GO) function, Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analyses, gene co-expression network analysis (WGCNA) and protein–protein interaction (PPI) network analysis were performed. Subsequently, the analyses of IL1B expression level, the Pearson correlation between IL1B and several COPD biomarkers were performed using other cohorts to validate our main findings.

Results

With a change ≥ twofold and P value < 0.05 cutoff, we found 38 genes were up-regulated and 114 genes were down-regulated in patients with COPD compared with health controls, while using cutoff fold change 1.5 and P value < 0.05, there were 318 genes up-regulated and 333 genes down-regulated. Among the most up-regulated genes were IL1B, CCL2, CCL23, and CXCL14, all implicated in inflammation triggering. GO, KEGG and WGCNA analysis all disclosed IL1B was highly correlated to COPD disease trait. The expression profile of IL1B was further validated using independent cohorts from COPD airway epithelium, lung tissue, sputum, and blood. We demonstrated higher IL1B gene expression in COPD small airway epithelial cells, but not in COPD lung tissue, sputum, and blood. Strong co-expression of IL1B with COPD biomarkers, such as DUOX2, MMP12, CCL2, and CXCL14, were validated in silico analysis. Finally, PPI network analysis using enriched data showed IL1B, CCL2, CCL7 and BMP7 were in the same hub node with high degrees.

Conclusions

We identified IL1B was significantly up-regulated in COPD small airway epithelial cells and propose IL1B as a novel player in airway inflammation in COPD.

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Abbreviations

IL1B:

Interleukin 1 beta

IL1R2:

Interleukin-1 receptor type 2

COPD:

Chronic obstructive pulmonary disease

CCL2:

Chemokine (C-C motif) ligand 2

CCL7:

Chemokine (C-C motif) ligand 7

CCL23:

Chemokine (C-C motif) ligand 23

HIF-1α:

Hypoxia inducible factor-1 alpha

DEGs:

Differentially expressed genes

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

ALDH3A1:

Aldehyde dehydrogenase 3 family, member A1

DUOX2:

Dual oxidase 2

MMP12:

Matrix metalloproteinase 12

AKR1B10:

Aldo–keto reductase family 1, member B10

CYP1B1:

Cytochrome P450 family 1 subfamily B polypeptide 1

NQO1:

NAD(P)H:quinoneoxidoreductase

PPI:

Protein–protein interaction

GS:

Gene significance

MM:

Module membership

GSEA:

Gene set enrichment analysis

IL17:

Interleukin-17

P450:

Cytochrome P450

GO:

Gene ontology

KEGG:

Kyoto Encyclopedia of Genes and Genomes

WGCNA:

Weighted Gene Co-expression Network Analysis

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Acknowledgements

We thank all members from department of central laboratory, the Fifth Affiliated Hospital of Guangzhou Medical University for their invaluable help.

Funding

This work was supported by the National Natural Science Foundation of China (Grant Number. 81400013), Science and Technology Planning Project of Guangdong Province, China (Grant Number. 2014A20212329) and Department of education of GuangDong Province, China (Grant Number. 2016KTSCX110).

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Author notes

  1. Gao Yi, Min Liang, and Ming Li are equal contributors.

Authors and Affiliations

  1. Department of Respiratory Medicine, State Key Laboratory of Respiratory Disease, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510700, China

    Gao Yi, Ming Li, Xiangming Fang, Jitao Chen, Chunyi Lin, Xinke Zhou & Zhaoyu Liu

  2. Department of Center Laboratory, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510700, China

    Gao Yi, Min Liang, Ming Li, Jifang Liu, Yuxiong Lai, Jitao Chen, Wenxia Yao, Xiao Feng, La Hu, Xinke Zhou & Zhaoyu Liu

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Contributions

ZYL, XKZ and JFL designed the study; ML (Min Liang), ML (Ming Li) and XMF performed data collection; GY and YXL analyzed the data; ZYL and GY wrote the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Xinke Zhou or Zhaoyu Liu.

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The authors declare that they have no competing interests.

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In the current study, all analyses were based on publicly available data, and this article does not contain any studies with human participants and animals performed by any of the authors.

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Responsible Editor: Liwu Li.

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Yi, G., Liang, M., Li, M. et al. A large lung gene expression study identifying IL1B as a novel player in airway inflammation in COPD airway epithelial cells. Inflamm. Res. 67, 539–551 (2018). https://doi.org/10.1007/s00011-018-1145-8

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  • DOI: https://doi.org/10.1007/s00011-018-1145-8

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